Spatial analysis of lung, colorectal, and breast cancer on Cape Cod: an application of generalized additive models to case-control data.
The availability of geographic information from cancer and birth defect registries has increased public demands for investigation of perceived disease clusters. Many neighborhood-level cluster investigations are methodologically problematic, while maps made from registry data often ignore latency and many known risk factors. Population-based case-control and cohort studies provide a stronger foundation for spatial epidemiology because potential confounders and disease latency can be addressed. We investigated the association between residence and colorectal, lung, and breast cancer on upper Cape Cod, Massachusetts (USA) using extensive data on covariates and residential history from two case-control studies for 1983-1993. We generated maps using generalized additive models, smoothing on longitude and latitude while adjusting for covariates. The resulting continuous surface estimates disease rates relative to the whole study area. We used permutation tests to examine the overall importance of location in the model and identify areas of increased and decreased risk. Maps of colorectal cancer were relatively flat. Assuming 15 years of latency, lung cancer was significantly elevated just northeast of the Massachusetts Military Reservation, although the result did not hold when we restricted to residences of longest duration. Earlier non-spatial epidemiology had found a weak association between lung cancer and proximity to gun and mortar positions on the reservation. Breast cancer hot spots tended to increase in magnitude as we increased latency and adjusted for covariates, indicating that confounders were partly hiding these areas. Significant breast cancer hot spots were located near known groundwater plumes and the Massachusetts Military Reservation. Spatial epidemiology of population-based case-control studies addresses many methodological criticisms of cluster studies and generates new exposure hypotheses. Our results provide evidence for spatial clustering of breast cancer on upper Cape Cod. The analysis suggests further investigation of the potential association between breast cancer and pollution plumes based on detailed exposure modeling.


The effect of ABO blood group and antibody class on the risk of COVID-19 infection and severity of clinical outcomes.
The COVID-19 pandemic has affected more than 100 million cases and caused immense burdens on governments and healthcare systems worldwide. Since its emergence in December 2019, research has been focused on treating the infected, identifying those at risk and preventing spread. There is currently no known biological biomarker that predicts the risk of infection. Several studies emerged suggesting an association between ABO blood group and the risk of COVID-19 infection. In this study, we used retrospective observational data in Bahrain to investigate the association between ABO blood group and risk of infection, as well as susceptibility to severe ICU-requiring infection. We found a higher risk associated with blood group B, and a lower risk with blood group AB. No association was observed between blood group and the risk of a severe ICU-requiring infection. We extended the analysis to study the association by antibodies; anti-a (blood groups B and O) and anti-b (blood groups A and O). No association between antibodies and both risk of infection or susceptibility to severe infection was found. The current study, along with the variation in blood group association results, indicates that blood group may not be an ideal biomarker to predict risk of COVID-19 infection.


Impact of rescue medication in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back pain.
Rescue medication (RM) consumption is commonly used as a secondary outcome in placebo-controlled trials of chronic pain, but its validity has yet to be established. If participants randomized to placebo take more RM than those randomized to an active drug, the difference in pain between the 2 groups may be reduced, potentially masking effects of the active drug. This study assessed proportional RM consumption in the placebo and active groups according to results of 42 randomized controlled trials of neuropathic pain (NeP), and 29 trials of low back pain, which were included in 2 systematic reviews and meta-analyses. Trial results were assessed based on effect size, statistical significance, and whether the drug was recommended as first-line treatment by the systematic reviews. In trials indicating effect of the investigational drug, RM consumption was generally higher in the placebo groups than in the active groups. In trials reporting a small or a medium effect size of the investigational drug, subjects receiving placebo consumed 17% to 30% more RM than subjects receiving active drug, potentially leading to underestimation of the effects of the investigational drugs. Few trials reported a large effect size. Differences in RM consumption between participants receiving placebo and those receiving active drug were seldom taken in account by the individual trials and not at all by the systemic reviews when making treatment recommendations for NeP or low back pain. Elaboration on analytical methods to assess treatment effects in chronic pain trials using RM is warranted.


Solar X-Ray Spectrum below 25 Angstroms.
Below 25 A, the solar spectrum consists primarily of the emission lines of Fe XVII, O VIII, O VII, and N VII. The lines of the more highly ionized atoms, Fe XVII and O VIII, originate in localized active regions. Lines of O VII and N VII emanate from the full disk.


Symbiotic flagellate protists as cryptic drivers of adaptation and invasiveness of the subterranean termite Reticulitermes grassei Clément.
Changes in flagellate protist communities of subterranean termite Reticulitermes grassei across different locations were evaluated following four predictions: (i) Rural endemic (Portugal mainland) termite populations will exhibit high diversity of symbionts; (ii) invasive urban populations (Horta city, Faial island, Azores), on the contrary, will exhibit lower diversity of symbionts, showing high similarity of symbiont assemblages through environmental filtering; (iii) recent historical colonization of isolated regions-as the case of islands-will imply a loss of symbiont diversity; and (iv) island isolation will trigger a change in colony breeding structure toward a less aggressive behavior. Symbiont flagellate protist communities were morphologically identified, and species richness and relative abundances, as well as biodiversity indices, were used to compare symbiotic communities in colonies from urban and rural environments and between island invasive and mainland endemic populations. To evaluate prediction on the impact of isolation (iv), aggression tests were performed among termites comprising island invasive and mainland endemic populations. A core group of flagellates and secondary facultative symbionts was identified. Termites from rural environments showed, in the majority of observed colonies, more diverse and abundant protist communities, probably confirming prediction (i). Corroborating prediction (ii), the two least diverse communities belong to termites captured inside urban areas. The Azorean invasive termite colonies had more diverse protist communities than expected and prediction (iii) which was not verified within this study. Termites from mainland populations showed a high level of aggressiveness between neighboring colonies, in contrast to the invasive colonies from Horta city, which were not aggressive to neighbors according to prediction (iv). The symbiotic flagellate community of R. grassei showed the ability to change in a way that might be consistent with adaptation to available conditions, possibly contributing to optimization of the colonization of new habitats and spreading of its distribution area, highlighting R. grassei potential as an invasive species.


Identification of the neural pathway for reinforcement of feeding when Aplysia learn that food is inedible.
Bilateral sectioning of the esophageal nerves that innervate the gut of Aplysia was found to have profound effect on response decrement to inedible food: Time to criterion for cessation of feeding was elevated, no memory of the decrement was present 24 hr after training, and motor patterning during training was altered. The parametric features of response decrement to sustained lip stimulation were examined to determine their resemblance to parameters of response decrement to inedible food after esophageal nerve sectioning. Parameters of response decrement were similar, indicating that after esophageal nerve sectioning response decrement is likely to be the result of sustained lip stimulation. Bilateral nerve sectioning had no effect on decrement due to sustained lip stimulation. Unilateral lesions and lesions of either of the two major divisions of the esophageal nerves had no effect on learning that food was inedible. The data indicate that bilateral nerve sectioning eliminates all stimuli causing negative reinforcement of feeding due to failure to consume food. Based on the data in this and the previous paper, a model is presented suggesting sites of action and mechanisms for learning that foods are edible or inedible in Aplysia.


The effect of a needle exchange program on numbers of discarded needles: a 2-year follow-up.
This study estimates the quantity and geographic distribution of discarded needles on the streets of Baltimore, Md, during the 2 years after a needle exchange program opened. Thirty-two city blocks were randomly sampled. Counts were taken of the number of syringes, drug vials, and bottles before the needle exchange program opened and then at 6 periodic intervals for 2 years after the program opened. Nonparametric and generalized estimating equation models were used to examine change over time. Two years after the needle exchange program opened, there was a significant decline in the overall quantity of discarded needles relative to that of drug vials and bottles (background trash). The block mean of number of needles per 100 trash items was 2.42 before the program opened and 1.30 2 years later (mean within-block change = -0.028, P < .05). There was no difference in the number of discarded needles by distance from the program site. These data suggest that this needle exchange program did not increase the number of distribution of discarded needles.


Description and Reliability of the AOSpine Sacral Classification System.
Several classification systems exist for sacral fractures; however, these systems are primarily descriptive, are not uniformly used, have not been validated, and have not been associated with a treatment algorithm or prognosis. The goal of the present study was to demonstrate the reliability of the AOSpine Sacral Classification System among a group of international spine and trauma surgeons. A total of 38 sacral fractures were reviewed independently by 18 surgeons selected from an expert panel of AOSpine and AOTrauma members. Each case was graded by each surgeon on 2 separate occasions, 4 weeks apart. Intrarater reproducibility and interrater agreement were analyzed with use of the kappa statistic (κ) for fracture severity (i.e., A, B, and C) and fracture subtype (e.g., A1, A2, and A3). Seventeen reviewers were included in the final analysis, and a total of 1,292 assessments were performed (646 assessments performed twice). Overall intrarater reproducibility was excellent (κ = 0.83) for fracture severity and substantial (κ = 0.71) for all fracture subtypes. When comparing fracture severity, overall interrater agreement was substantial (κ = 0.75), with the highest agreement for type-A fractures (κ = 0.95) and the lowest for type-C fractures (κ = 0.70). Overall interrater agreement was moderate (κ = 0.58) when comparing fracture subtype, with the highest agreement seen for A2 subtypes (κ = 0.81) and the lowest for A1 subtypes (κ = 0.20). To our knowledge, the present study is the first to describe the reliability of the AOSpine Sacral Classification System among a worldwide group of expert spine and trauma surgeons, with substantial to excellent intrarater reproducibility and moderate to substantial interrater agreement for the majority of fracture subtypes. These results suggest that this classification system can be reliably applied to sacral injuries, providing an important step toward standardization of treatment.


Nitrogen heterocycles via palladium-catalyzed carbocyclization. Formal synthesis of (+)-alpha-allokainic acid.
[reaction: see text] The Pd-catalyzed carbocyclization of ketoamides was investigated and found to be highly dependent on the phosphine ligand as well as the presence of coordinating counterions. Nitrogen heterocycles were formed without erosion of the stereochemical integrity. The utility of the lactam products was demonstrated by the formal synthesis of (+)-alpha-allokainic acid.


In vivo visualization of F-actin structures during the development of the moss Physcomitrella patens.
* The 'in planta' visualization of F-actin in all cells and in all developmental stages of a plant is a challenging problem. By using the soybean heat inducible Gmhsp17.3B promoter instead of a constitutive promoter, we have been able to label all cells in various developmental stages of the moss Physcomitrella patens, through a precise temperature tuning of the expression of green fluorescent protein (GFP)-talin. * A short moderate heat treatment was sufficient to induce proper labeling of the actin cytoskeleton and to allow the visualization of time-dependent organization of F-actin structures without impairment of cell viability. * In growing moss cells, dense converging arrays of F-actin structures were present at the growing tips of protonema cell, and at the localization of branching. Protonema and leaf cells contained a network of thick actin cables; during de-differentiation of leaf cells into new protonema filaments, the thick bundled actin network disappeared, and a new highly polarized F-actin network formed. * The controlled expression of GFP-talin through an inducible promoter improves significantly the 'in planta' imaging of actin.


[Syntopy of the pancreas].
Resulting from the examination of 309 patients, the author has established that the pancreas could displace to the region of the lesser sac with ensuing impairement of the blood outflow through the mesenteric veins. This causes the development of venous circulation disease of the abdominal organs.


[The relationship of vascular changes and immune status disorders in patients with diabetes mellitus type 1].
Immunologic status was studied in 86 patients with type-I diabetes mellitus before and after treatment with decarise, thymaline and T-activin. With the aid of ECG, phonocardiogramme, apex cardiogramme, oscillogramme, there has been calculated index of vitality of the myocardium reflecting the subendocardial bloodflow. The principal parameters characterising bodily immune status (absolute number of T- and B-lymphocytes), T-suppressors counts as well as those of circulating immune complexes (CIC) were compared to the values for subendocardial bloodflow (end-diastolic pressure, index of vitality of the myocardium). There has been established strong inverse relation between the absolute numbers of T-, B-lymphocytes, and CIC, end-diastolic pressure and index of vitality of the myocardium, this being regarded as evidence in confirmation of the guarding role of the former and damaging one of the latter (CIC) under vascular pathology in diabetes mellitus.


Highly luminescent-paramagnetic nanophosphor probes for in vitro high-contrast imaging of human breast cancer cells.
Highly luminescent-paramagnetic nanophosphors have a seminal role in biotechnology and biomedical research due to their potential applications in biolabeling, bioimaging, and drug delivery. Herein, the synthesis of high-quality, ultrafine, europium-doped yttrium oxide nanophosphors (Y(1.9)O(3):Eu(0.1)(3+)) using a modified sol-gel technique is reported and in vitro fluorescence imaging studies are demonstrated in human breast cancer cells. These highly luminescent nanophosphors with an average particle size of ≈6 nm provide high-contrast optical imaging and decreased light scattering. In vitro cellular uptake is shown by fluorescence microscopy, which visualizes the characteristic intense hypersensitive red emission of Eu(3+) peaking at 610 nm ((5)D(0)-(7)F(2)) upon 246 nm UV light excitation. No apparent cytotoxicity is observed. Subsequently, time-resolved emission spectroscopy and SQUID magnetometry measurements demonstrate a photoluminescence decay time in milliseconds and paramagnetic behavior, which assure applications of the nanophosphors in biomedical studies.


Impact of anemia on mortality, cognition, and function in community-dwelling elderly.
To explore the impact of varying hemoglobin levels on mortality, function, and cognition in a representative population of older persons. Participants in this prospective cohort study included 1 744 men and women, aged 71 years or older, from a random household sample living in Durham and surrounding counties in North Carolina. Hemoglobin levels were obtained from participants at baseline in 1992. Functional status was measured at the 4-year follow-up interview using Katz and instrumental activities of daily living. Cognition was measured using the Short Portable Mental Status Questionnaire (SPMSQ). Death was determined by search of the National Death Index, and all deaths through 2000 are included. Using World Health Organization (WHO) criteria, the prevalence of anemia was 24%. There was a strong racial difference with an odds ratio, adjusted for age, education, estimated glomerular filtration rate and comorbidity of 3.0 (95% CI, 2.3-3.9) in African Americans compared with Caucasians. The risk ratio for 8-year mortality was 1.7 (95% CI, 1.5-2.0) for anemic subjects (P = .0001) and did not differ by sex or race. Anemia was strongly associated with poorer physical function (P = .0001) and cognitive function (P = .0001), and predicted decreases in both over a 4-year period. In an elderly community-based population, anemia is more prevalent in African Americans and is independently associated with increased mortality over 8 years for both races and sexes. Anemia also is a risk factor for functional and cognitive decrease.


Osteoporosis, calcium and physical activity.
Sales of calcium supplements have increased dramatically since 1983, as middle-aged women seek to prevent or treat bone loss due to osteoporosis. However, epidemiologic studies have failed to support the hypothesis that larger amounts of calcium are associated with increased bone density or a decreased incidence of fractures. The authors examine the evidence from controlled trials on the effects of calcium supplementation and physical activity on bone loss and find that weight-bearing activity, if undertaken early in life and on a regular basis, can increase the peak bone mass of early adulthood, delay the onset of bone loss and reduce the rate of loss. All of these factors will delay the onset of fractures. Carefully planned and supervised physical activity programs can also provide a safe, effective therapy for people who have osteoporosis.


Thrombophilia, hypofibrinolysis, the eNOS T-786C polymorphism, and multifocal osteonecrosis.
We examined the hypothesis that thrombophilia, hypofibrinolysis, and the endothelial nitric oxide synthase (eNOS) T-786C polymorphism are common, potentially treatable, and similar pathophysiologic causes of multifocal (three sites or more) and unifocal (single-site) osteonecrosis. We prospectively evaluated twenty-six consecutively referred adults with multifocal osteonecrosis, who included thirteen with idiopathic multifocal osteonecrosis and thirteen with secondary multifocal osteonecrosis (resulting from steroid therapy in ten and alcoholism in three). We compared these patients with race, sex, and age-matched normal control subjects and with patients with idiopathic unifocal and secondary unifocal osteonecrosis, respectively. Using polymerase chain reaction and serologic measures, we studied thrombophilic and hypofibrinolytic mutations and the eNOS T-786C polymorphism. The total number of polymerase chain reaction and serologic thrombophilic-hypofibrinolytic abnormalities and the eNOS T-786C polymorphism did not differ between patients with idiopathic (p > 0.5) or secondary (p > 0.5) multifocal and unifocal osteonecrosis. The frequency of low free protein-S levels (<66%) in patients with secondary multifocal osteonecrosis (four of eleven patients) was higher than that in the control subjects (one of fifty-nine) (risk ratio = 21.5; 95% confidence interval, 2.6 to 174; p = 0.0016, Benjamini-Hochberg adjusted p [Bp] = 0.004). Factor-V Leiden heterozygosity was present in two of thirteen patients with secondary multifocal osteonecrosis compared with none of sixty-four control subjects (p = 0.027, Bp = 0.008). For eleven patients with secondary multifocal osteonecrosis, the eNOS T-786C polymorphism was present in nine of twenty-two alleles compared with eight of forty-four alleles in twenty-two normal control subjects (risk ratio = 2.3; 95% confidence interval, 1.0 to 5.0; p = 0.047, Bp = 0.016). The frequency of homocystinemia (>13.5 mumol/L) was higher in patients with idiopathic multifocal osteonecrosis (two of thirteen patients) than in normal controls (none of fifty-one) (p = 0.039, Bp = 0.004). A high level of factor VIII (>150%) was seen in four of eight patients with idiopathic multifocal osteonecrosis and in seven of forty-eight normal controls (risk ratio = 3.4; 95% confidence interval, 1.3 to 9.1; p = 0.04, Bp = 0.008). The eNOS T-786C mutant allele was present in seven of twelve alleles in the six patients with idiopathic multifocal osteonecrosis who were tested, compared with twenty-five of 108 alleles in fifty-four control subjects (risk ratio = 2.5; 95% confidence interval, 1.4 to 4.5; p = 0.015, Bp = 0.008). Limited by the small numbers of patients with multifocal osteonecrosis, this exploratory study suggested that thrombophilia was associated with both idiopathic multifocal osteonecrosis and secondary multifocal osteonecrosis, as was the eNOS T-786C polymorphism. Multifocal and unifocal osteonecrosis are similarly associated with thrombophilia, hypofibrinolysis, and the eNOS T-786C polymorphism, which are potentially treatable pathophysiologic conditions, requiring further study.


Multiple-object 2-D-3-D registration for noninvasive pose identification of fracture fragments.
This paper presents a multiple-object 2-D-3-D registration technique for noninvasively identifying the poses of fracture fragments in the space of a preoperative treatment plan. The plan is made by manipulating and aligning computer models of individual fracture fragments that are segmented from a diagnostic computed tomography. The registration technique iteratively updates the treatment plan and matches its digitally reconstructed radiographs to a small number of intraoperative fluoroscopic images. The proposed approach combines an image similarity metric that integrates edge information with mutual information, and a global-local optimization scheme, to deal with challenges associated with the registration of multiple small fragments and limited imaging orientations in the operating room. The method is easy to use as minimum user interaction is required. Experiments on simulated fractures and two distal radius fracture phantoms demonstrate clinically acceptable target registration errors with capture range as large as 10 mm.


Use of Platelet-Rich Plasma in Intra-Articular Knee Injections for Osteoarthritis: A Systematic Review.
To systematically analyze the literature on the use of platelet-rich plasma (PRP) for intra-articular injections of the knee and its efficacy in the treatment of knee osteoarthritis (OA). Systematic literature reviews were conducted in PubMed, Embase, and CINAHL (ie, Cumulative Index to Nursing and Allied Health Literature) on October 30, 2013, using the keywords "platelet-rich plasma" and "knee" and "osteoarthritis." Inclusion criteria included (1) studies with human subjects, (2) prospective clinical studies (including either clinical trials or observational studies), and (3) full-text articles published in English. Exclusion criteria were: (1) animal studies; (2) retrospective studies; (3) patients with previous surgical intervention with total knee arthroplasty or reconstruction of the anterior cruciate ligaments; and (4) articles not published in English A total of 319 abstracts and titles were reviewed (60 from PubMed, 250 from Embase, and 9 from CINAHL). A total of 8 relevant journal articles were identified, all of which were published between 2010 and 2013. One-half of the studies were prospective observational studies that included only PRP treatment; the rest were prospective comparative studies including both PRP and controls-2 were randomized controlled trials. Of the 4 comparative studies, 3 compared PRP with hyaluronic acid, which was considered as a commonly used effective treatment for knee OA; the other one used saline injection (ie, placebo) as the control. Although most of the analyses suffered from small sample size and was thus inconclusive, the findings consistently indicated that PRP might have better outcomes in patients with a lesser degree of degeneration and in younger patients. PRP intra-articular injections of the knee may be an effective alternative treatment for knee OA. However, current studies are at best inconclusive regarding the efficacy of the PRP treatment. A large, multicenter randomized trial study is needed to further assess the efficacy of PRP treatment for patients with knee OA.


Perceived Treatment Need and Latent Transitions in Heroin and Methamphetamine Polydrug Use among People who Inject Drugs in Tijuana, Mexico.
People who inject drugs (PWID) in Tijuana, Mexico, use heroin and/or methamphetamine. While polydrug use is associated with HIV risk behavior, less is known about the stability of polydrug use patterns over time and how polydrug use is related to perceived treatment need. Within a cohort of PWID in Tijuana (N = 735) we sought to (1) characterize subgroups of polydrug and polyroute use from baseline to six months; (2) determine the probabilities of transitioning between subgroups; and (3) examine whether self-reported need for help for drug use modified these transition probabilities. Latent transition analysis (LTA) identified four latent statuses: heroin-only injection (38% at both baseline and follow-up); co-injection of heroin with methamphetamine (3% baseline, 15% follow-up); injection of heroin and methamphetamine (37% baseline, 32% follow-up); and polydrug and polyroute users who injected heroin and both smoked and injected methamphetamine (22% baseline, 14% follow-up). Heroin-only injectors had the highest probability of remaining in the same latent status at follow-up. The majority reported great or urgent need for treatment (51%) and these PWID had greater odds of transitioning to a higher-risk status at follow-up, emphasizing the need for evidence-based drug treatment options for PWID.


Hydrophobic compounds reshape membrane domains.
Cell membranes have a complex lateral organization featuring domains with distinct composition, also known as rafts, which play an essential role in cellular processes such as signal transduction and protein trafficking. In vivo, perturbations of membrane domains (e.g., by drugs or lipophilic compounds) have major effects on the activity of raft-associated proteins and on signaling pathways, but they are difficult to characterize because of the small size of the domains, typically below optical resolution. Model membranes, instead, can show macroscopic phase separation between liquid-ordered and liquid-disordered domains, and they are often used to investigate the driving forces of membrane lateral organization. Studies in model membranes have shown that some lipophilic compounds perturb membrane domains, but it is not clear which chemical and physical properties determine domain perturbation. The mechanisms of domain stabilization and destabilization are also unknown. Here we describe the effect of six simple hydrophobic compounds on the lateral organization of phase-separated model membranes consisting of saturated and unsaturated phospholipids and cholesterol. Using molecular simulations, we identify two groups of molecules with distinct behavior: aliphatic compounds promote lipid mixing by distributing at the interface between liquid-ordered and liquid-disordered domains; aromatic compounds, instead, stabilize phase separation by partitioning into liquid-disordered domains and excluding cholesterol from the disordered domains. We predict that relatively small concentrations of hydrophobic species can have a broad impact on domain stability in model systems, which suggests possible mechanisms of action for hydrophobic compounds in vivo.


MPYS/STING-mediated TNF-α, not type I IFN, is essential for the mucosal adjuvant activity of (3'-5')-cyclic-di-guanosine-monophosphate in vivo.
The bacterial second messenger (3'-5')-cyclic-di-guanosine-monophosphate (CDG) is a promising mucosal adjuvant candidate that activates balanced Th1/Th2/Th17 responses. We showed previously that CDG activates stimulator of IFN genes (STING)-dependent IFN-I production in vitro. However, it is unknown whether STING or IFN-I is required for the CDG adjuvant activity in vivo. In this study, we show that STING(-/-) mice (Tmem173(<tm1Camb>)) do not produce Ag-specific Abs or Th1/Th2/Th17 cytokines during CDG/Ag immunization. Intranasal administration of CDG did not induce TNF-α, IL-1β, IL-6, IL-12, or MCP-1 production in STING(-/-) mice. Surprisingly, we found that the cytokine and Ab responses were unaltered in CDG/Ag-immunized IFNAR(-/-) mice. Instead, we found that CDG activates STING-dependent, IFN-I-independent TNF-α production in vivo and in vitro. Furthermore, using a TNFR1(-/-) mouse, we demonstrate that TNF-α signaling is critical for CDG-induced Ag-specific Ab and Th1/Th2 cytokine production. This is distinct from STING-mediated DNA adjuvant activity, which requires IFN-I, but not TNF-α, production. Finally, we found that CDG activates STING-dependent, but IRF3 stimulation-independent, NF-κB signaling. Our results established an essential role for STING-mediated TNF-α production in the mucosal adjuvant activity of CDG in vivo and revealed a novel IFN-I stimulation-independent STING-NF-κB-TNF-α pathway.


Kinetic and phenotypic changes in murine lymphocytes infected with murine gammaherpesvirus-68 in vitro.
Primary infection with murine gammaherpesvirus-68 (MHV-68), as with other members of the gammaherpesvirus subfamily, is characterized by a lymphoproliferative phase. MHV-68 causes acute splenomegaly and an infectious mononucleosis-like syndrome in which there is expansion of the CD8+ T cell subset. In long-term infections, MHV-68 is associated with lymphoma development. In order to elucidate the mechanisms underlying the proliferative processes, the events following infection of murine splenocytes or purified murine B lymphocytes in vitro have been examined. MHV-68 infection prolonged the viability of murine splenocytes and stimulated cellular proliferation. Unlike Epstein-Barr virus and herpesvirus saimiri, MHV-68 did not cause growth transformation. Growth transformation did not occur even when cells with a predisposition to transformation were infected or when culture conditions were selected to enhance the viability of the cells. Following MHV-68 infection, the latency-associated viral tRNAs were transcribed. However, transcription of the other known latency-associated gene, M2, was not observed. In addition, there was no evidence of productive virus replication either by staining with antibodies specific for late virus antigens or by in situ hybridization for early and late mRNAs. In contrast to Epstein-Barr virus- and herpesvirus saimiri-infected lymphocytes, where episomal genomes are seen, Gardella gel analysis indicated that the primary lymphocytes infected by MHV-68 in vitro contained only linear virus DNA. This DNA was nuclease sensitive, indicating that, while MHV-68 was efficiently uncoated, its circularization in vitro was extremely inefficient. These results are discussed in terms of the host-virus interaction.


Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4.
Adaptive immunity depends on specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (pMHC) molecule on an antigen-presenting cell (APC). In addition, T-cell activation generally requires binding of this same pMHC to a CD4 or CD8 coreceptor. Here, we report the structure of a complete TCR-pMHC-CD4 ternary complex involving a human autoimmune TCR, a myelin-derived self-peptide bound to HLA-DR4, and CD4. The complex resembles a pointed arch in which TCR and CD4 are each tilted ∼65° relative to the T-cell membrane. By precluding direct contacts between TCR and CD4, the structure explains how TCR and CD4 on the T cell can simultaneously, yet independently, engage the same pMHC on the APC. The structure, in conjunction with previous mutagenesis data, places TCR-associated CD3εγ and CD3εδ subunits, which transmit activation signals to the T cell, inside the TCR-pMHC-CD4 arch, facing CD4. By establishing anchor points for TCR and CD4 on the T-cell membrane, the complex provides a basis for understanding how the CD4 coreceptor focuses TCR on MHC to guide TCR docking on pMHC during thymic T-cell selection.


Differences in the execution/nonexecution of advance directives by community dwelling adults.
Factors associated with the process of execution or nonexecution of advance directives, that is, living wills and/or durable powers of attorney for health care, by community dwelling adults are described. Data were collected by mail (n = 210, 51% response rate); 18.1% (n = 38) had executed an advance directive (AD). Significant differences were noted between AD executors and nonexecutors. Executors were older than nonexecutors. Executors had greater concern about an executed AD diminishing the quality of care they received. They participated in more MD-initiated discussions about ADs, and had more numerous AD educational experiences, more personal experience with the terminal illnesses or critical injuries of relatives or friends, a greater degree of familiarity with AD documents, and a greater degree of religiosity. The integration of these factors at various points along a continuum of intentional self-change moves an individual through several stages of a behavioral change process, culminating with the execution or nonexecution of an AD.


Towards a Clinical Efficacy Evaluation System Adapted for Personalized Medicine.
The rise of precision medicine (PM) has initiated the transition of mainstream medicine from disease-based medicine to personalized medicine, alongside which the US FDA has begun to establish a clinical trial and efficacy evaluation (CTEE) system compatible with personalized medicine based on biological markers. Outside of modern medicine, however, there has always existed a personalized medical system, traditional Chinese medicine (TCM), that is, a personalized medical system built at the organism level with a similar concept and method to today's complexity science. However, under the current CTEE system, TCM has not usually been shown to be effective. The CTEE system of modern medicine has now begun to embrace personalized medicine at the microlevel. Therefore, there is no reason to continue to reject TCM, which is a type of personalized medicine at the organism level. This paper analyzes and compares the commonality and differences between a personalized medical system based on biomarkers established by PM and a personalized medical system based on syndromes in TCM; the results clearly reveal structural relationships between the two medical systems. On this basis, through rigorous logical reasoning, the feasibility of applying the CTEE method which is used in PM to evaluate the efficacy of TCM treatments is demonstrated. The relationship among biomarkers by which PM describes personalized states and modern medical diseases and the relationship among TCM syndromes and diseases are completely consistent. Because of this consistency, the new CTEE system established by the US FDA to promote the development of PM is fully applicable to the clinical trial and efficacy evaluation of TCM treatment methods. Clinical trials and efficacy evaluations based on this system can scientifically prove the effectiveness of TCM, and TCM is expected to be incorporated into the modern medical system based on scientific norms.


Pembrolizumab or Placebo Plus Chemotherapy With or Without Bevacizumab for Persistent, Recurrent, or Metastatic Cervical Cancer: Subgroup Analyses from the KEYNOTE-826 Randomized Clinical Trial.
The KEYNOTE-826 randomized clinical trial showed statistically significant and clinically meaningful survival benefits with the addition of pembrolizumab to chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. Treatment effects in patient subgroups of the study population are unknown. To assess efficacy outcomes in patient subgroups of KEYNOTE-826. Exploratory subgroup analyses were conducted in a global, phase 3, randomized, double-blind, placebo-controlled clinical trial. Participants included women with persistent, recurrent, or metastatic adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma of the cervix that had not been treated with systemic chemotherapy and was not amenable to curative treatment. This subanalysis was conducted from November 20, 2018, to May 3, 2021. Pembrolizumab, 200 mg, every 3 weeks or placebo for up to 35 cycles plus chemotherapy (paclitaxel, 175 mg/m2, plus cisplatin, 50 mg/m2, or carboplatin AUC 5 [area under the free carboplatin plasma concentration vs time curve]) with or without bevacizumab, 15 mg/kg. Overall survival (OS) and progression-free survival (PFS) by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 in subgroups defined by use of bevacizumab (yes or no), choice of platinum (carboplatin or cisplatin), prior chemoradiotherapy (CRT) exposure only (yes or no), and histologic type (squamous or nonsquamous) in patients with programmed cell death ligand 1-positive tumors (defined as a combined positive score [CPS] ≥1) and in the intention-to-treat population. A total of 617 patients (median age, 51 years; range, 22-82 years) were enrolled in the trial. In the CPS greater than or equal to 1 population, hazard ratios (HRs) for OS favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.62; 95% CI, 0.45-0.87) and without bevacizumab (HR, 0.67; 95% CI, 0.47-0.96), use of carboplatin (HR, 0.65; 95% CI, 0.50-0.85) and cisplatin (HR, 0.53; 95% CI, 0.27-1.04), with prior CRT only (HR, 0.56; 95% CI, 0.39-0.81) and without prior CRT only (HR, 0.72; 95% CI, 0.52-1.00), and squamous (HR, 0.60; 95% CI, 0.46-0.79) and nonsquamous (HR, 0.70; 95% CI, 0.41-1.20) histologic type. In the intention-to-treat population, HRs for OS also favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.63; 95% CI, 0.47-0.87) and without bevacizumab (HR, 0.74; 95% CI, 0.53-1.04), use of carboplatin (HR, 0.69; 95% CI, 0.54-0.89) or cisplatin (HR, 0.59; 95% CI, 0.32-1.09), with prior CRT only (HR, 0.64; 95% CI, 0.45-0.91) and without prior CRT only (HR, 0.71; 95% CI, 0.53-0.97), and squamous (HR, 0.61; 95% CI, 0.47-0.80) and nonsquamous (HR, 0.76; 95% CI, 0.47-1.23) histologic type. Similar to OS, the addition of pembrolizumab prolonged PFS across all subgroups in the CPS greater than or equal to 1 and intention-to-treat populations. The findings of this trial suggest that adding pembrolizumab to chemotherapy with or without bevacizumab improved OS across subgroups of patients with persistent, recurrent, or metastatic cervical cancer. ClinicalTrials.gov Identifier: NCT03635567.


A homology model for human alpha-l-iduronidase: insights into human disease.
Genotype-phenotype correlations in genetic diseases for which missense mutations lead to disease remain a challenge. This is particularly true for diseases caused by alterations of proteins for which no three-dimensional structure is available. One such disease is Mucopolysaccharidosis type I, a disorder arising from a lack of activity of the lysosomal enzyme alpha-l-iduronidase (IDUA, EC 188.8.131.52). This deficiency compromises the degradation pathway of glycosaminoglycans such as heparan sulfate and dermatan sulfate, leading to substrate accumulation, which ultimately results in a multisystem disorder. Patients with IDUA deficiency have a wide spectrum of disease ranging from an early onset, rapidly progressive form leading to death in the first decade of life, to an attenuated disease which manifests in adolescence and leads to progressive joint and cardiac disease but is associated with a normal life span. Many patients fit into a disease phenotype intermediate to these extremes. While a number of point mutations have been described as leading to varying degrees of disease severity, a structural basis for these genotype-phenotype correlations has not been available owing to the lack of a three-dimensional structure for IDUA. A homology model for the IDUA enzyme was constructed based on the recently solved crystal structure of the beta-xylosidase from Thermoanaerobacterium saccharolyticum (XyTS, EC 18.104.22.168), both of which belong to the same sequence-related family (CAZY family 39). This model provides insights into why certain point mutations produce severely misfolded proteins and thus lead to severe disease, and why other mutations produce proteins with only minor structural perturbations and therefore the attenuated form of the disease.


Emerging molecular biomarkers--blood-based strategies to detect and monitor cancer.
There is an urgent need for blood-based, noninvasive molecular tests to assist in the detection and diagnosis of cancers in a cost-effective manner at an early stage, when curative interventions are still possible. Additionally, blood-based diagnostics can classify tumors into distinct molecular subtypes and monitor disease relapse and response to treatment. Increasingly, biomarker strategies are becoming critical to identify a specific patient subpopulation that is likely to respond to a new therapeutic agent. The improved understanding of the underlying molecular features of common cancers and the availability of a multitude of recently developed technologies to interrogate the genome, transcriptome, proteome and metabolome of tumors and biological fluids have made it possible to develop clinically applicable and cost-effective tests for many common cancers. Overall, the paradigm shift towards personalized and individualized medicine relies heavily on the increased use of diagnostic biomarkers and classifiers to improve diagnosis, management and treatment. International collaborations, involving both the private and public sector will be required to facilitate the development of clinical applications of biomarkers, using rigorous standardized assays. Here, we review the recent technological and scientific advances in this field.


Chronic thromboembolic pulmonary hypertension anno 2021.
In the past decades, the diagnostic and therapeutic management of chronic thromboembolic pulmonary hypertension (CTEPH) has been revolutionized. Advances in epidemiological knowledge and follow-up studies of pulmonary embolism patients have provided more insight in the incidence and prevalence. Improved diagnostic imaging techniques allow accurate assessment of the location and extend of the thromboembolic burden in the pulmonary artery tree, which is important for the determination of the optimal treatment strategy. Next to the pulmonary endarterectomy, the newly introduced technique percutaneous pulmonary balloon angioplasty and/or P(A)H-targeted medical therapy has been shown to be beneficial in selected patients with CTEPH and might also be of importance in patients with chronic thromboembolic pulmonary vascular disease. In this era of a comprehensive approach to CTEPH with different treatment modalities, a multidisciplinary approach guides management decisions leading to optimal treatment and follow-up of patients with CTEPH.


Depression in the US population during the time periods surrounding the great recession.
To determine whether the time periods surrounding the 2008 US economic downturn were accompanied by an increase in prevalence of depression in the US adult population. We used data from the 24,182 adults aged ≥ 18 years who participated in the National Health and Nutrition Examination Survey during 2005-2012. A cross-sectional analysis was performed at each time period to determine prevalence of major and other depression as assessed by standardized questionnaires based on 9 criteria for major depressive episodes defined by DSM-IV. The demographic characteristics of the US population were similar across time periods except for the percentage of adults living in poverty, which increased from 26.43% during 2005-2006 to 33.46% during 2011-2012. The prevalence of major depression increased from 2.33% (95% CI, 1.64%-3.01%) during 2005-2006 to 3.49% (95% CI, 2.84%-4.03%) in 2009-2010 to 3.79% (95% CI, 3.01%-4.57%) in 2011-2012. Prevalence of other depression increased from 4.10% (95% CI, 3.37%-4.88%) in 2005-2006 to 4.79% (95% CI, 4.10%-5.44%) in the 2009-2010 period but then declined to 3.68% (95% CI, 2.84%-4.48%) in the 2011-2012 time period (P = .4). After adjustment for the distribution of age, sex, race/ethnicity, education, insurance status, and poverty status in the US adult noninstitutionalized population, each 2-year period after the 2005-2006 time period was associated with a 0.4% increase in major depression prevalence (P < .001). No significant differences in other depression prevalence were noted by time period (P = .6). The time periods surrounding the recent economic recession were accompanied by a significant and sustained increase in major depression prevalence in the US population. It is plausible that the recession, given its strong, persistent, and negative effects on employment, job and housing security, and stock investments, contributed to the sustained increase in prevalence of major depression in the US population, but other factors associated with the recession time period could have played a role. The impact of the economic downturn on depression prevalence should be considered when formulating future policies and programs to promote and maintain the health of the US population.


Diagnosis and treatment of extreme lateral lumbar disc herniation.
Extreme lateral lumbar disc herniation is located in the foramen and compresses the exiting root producing symptoms attributed to the upper nerve root of the involved disc and vertebral level. The diagnosis is best established by using magnetic resonance imaging which visualizes the foramen in an axial and sagittal plane. Surgical treatment may be varied, but a posterior midline approach with drilling of the pars interarticularis will easily expose the nerve root and the herniated disc in the foramen. Results are usually excellent, with resolution of radicular pain.


Reaction of the 1,8-bis(diphenylmethylium)naphthalenediyl dication with fluoride: formation of a cation containing a C-F-->C bridge.
Treatment of 1,8-bis(diphenylhydroxymethyl)naphthalene with a mixture of [HBF(4)](aq) and (CF(3)CO)(2)O affords the corresponding dication, 1,8-bis(diphenylmethylium)naphthalenediyl (1(2+)), which was isolated as the [BF4]- salt. This dication has been fully characterized, and its structure has been studied computationally. The (13)C NMR resonance of the methylium centers appears at 207.7 ppm. As indicated by an X-ray single-crystal analysis, the vicinal methylium centers are separated by 3.112(4) A. Dication (1(2+)) reacts with fluoride to afford [1-F]+ which has been isolated as the [BF4]- salt. The fluorine atom of [1-F](+) is connected to one of the former methylium centers through a typical C-F bond of 1.424(2) A and forms a long interaction of 2.444(2) A with the other methylium center. While the structure of [1-F]+ can be largely accounted for by considering a simple methylium formulation, density functional calculations followed by an Atom In Molecules analysis as well as a calculation of the Boys localized orbitals indicate that the long C-F interaction of 2.444(2) A corresponds to a dative bond. Hence, formulation of [1-F]+ as an unsymmetrical fluoronium must also be considered. As indicated by 1H NMR spectroscopy, the structure of this ion is fluxional; the fluorine atom oscillates between the former methylium centers with apparent activation parameters of DeltaH++ = 52(+/-3) kJ mol(-1) and DeltaS++ = -18(+/-9) J K(-1) mol(-1) as derived from line shape analysis. This dynamic process, which has also been studied theoretically by B3LYP density functional theory and Møller-Plesset second-order perturbation theory methods, involves symmetrical fluoronium ions as low-energy transition states.


Obstructive perianal lesion in a 75-year-old man.
A 75-year-old man presented with a fungating peri-anal mass which appeared malignant at presentation and required a defunctioning colostomy due to abdominal distension. Multiple biopsies were negative for malignancy and CT/MRI scans showed no malignant mass. A provisional diagnosis of prolapsed haemorrhoids was made and the mass was treated with sugar and charcoal dressings. There was a dramatic resolution of the mass with this treatment and the patient was discharged 1 month post-admission. The patient then underwent an elective haemorrhoidectomy by which time the mass had decreased to a perianal skin tag. The only clues in this case were the acute presentation of the mass, the fact that the mass had appeared post-defecation and that the patient had been diagnosed with haemorrhoids 2 years previously on colonoscopy. This case highlights the importance of evaluating all investigations and considering all differential diagnoses before embarking on definitive management.


[Decrease in efficiency after experimental virus encephalitis. Small scale experimental tests on mice and histologic evaluation (author's transl)].
Two different experiments were set up in order to test the efficiency of 281 mice which had been infected intracerebrally with yellow fever virus 17 D of various dilutions (10(-1)-10(-5)); the tests were run after two time periods (40--55 days after infection = I. date, and 97 and 160 days after infection = II. date). In the first experimental set-up the animals were to find their food in a labyrinth- after 24 hours without food, (Labyrinth Experiment, Fig. 1). The time was taken from the moment when the mouse was put into the cage until the moment when it ate from the food. 4.37 min, were considered to be "standard time". In the second experiment the mice were placed on a horizontal rod rotating round an axle (Rotating Rod Experiment, Fig. 2 a,b,c). The time was measured for how long the animals could stay on the rod. 90/10 sec., were ascertained as "standard time". The following results were obtained. The difference in time regarding the I. and II. date is clearly noticed by the experiment with the rotating rod. The performance time of the animals was almost doubled after the 2nd time period (Table 4a and b, Fig. 3a and b), i.e. the animals could stay on the rod almost twice as long as after the first time period, which means that the recovery process of the animals can be measured by means of the rod experiment. In this respect the experiment with the labyrinth is less suitable. The recovery of the animals as well as the residual damages depended on the inoculated virus dilutions (Table 5a and b, Fig. 4a and b, Tables 7 and 8, Fig 21a and b). The histologic findings of the animals show lesions in all regions of the Central Nerve System (Fig 6-20, Table 2). The deficiencies of the animals which are due to diffuse damages of the Central Nerve System are demonstrated by the rotating rod experiment, whereas the labyrinth experiment verifies the shortcomings of the cornu ammonis (olfactory brain). The rotating rod experiment is the more sensitive of the two models as the majority of the lesions are distributed diffusely on the Central Nervous System. The severe lesions of the Central Nerve System which are supported by histologic findings - even 160 days after infection, are confirmed by the deficiencies in the performance processes of the animals (delayed damages). Discussion have taken place regarding whether the experimental results of the animals can be applied to assessing latent or delayed damages in children after an encephalitis. The latter could concern in how far the course of an encephalitis depends on the originating virus dosis and could also relate to the development of delayed damages. The knowledge regarding the formation of delayed damages, their assessment as well as the prevention of encephalitis in infants would thus be greatly improved. In order to judge therapeutic measures on animals the rotating rod experiment appears to be very suitable since each stage of the illness enables an assessment of the state of the disease.


Antiepileptogenic effects of conventional anticonvulsants in the kindling model of epilespy.
We sought to determine whether the clinically effective anticonvulsant drug valproate exhibited antiepileptogenic properties in the kindling model (we use the term anticonvulsant to mean suppression of seizure, and antiepileptogenic to mean suppression of development of epilepsy). We compared and contrasted valproate with two other anticonvulsant drugs, phenobarbital and carbamazepine. We investigated the effects of these drugs on the development of kindling, that is, the number of stimulation-induced afterdischarges required to induce enhanced seizure susceptibility in rats. Valproate exhibited powerful antiepileptogenic effects as evident in a dose-dependent increase in the number of afterdischarges required to induce kindling. These effects were not due to retained valproate or an active metabolite merely masking the expression of kindled seizures. By contrast, carbamazepine was devoid of any antiepieptogenic effects despite exhibiting marked anticonvulsant effects. Like valproate, phenobarbital exhibited both antiepileptogenic and anticonvulsant properties, but its antiepileptogenic properties were significantly less pronounced. The antiepileptogenic effects of valproate and phenobarbital strengthen the candidacy of these agents for the clinical studies needed to investigate pharmacological prevention of the development of epilepsy in high-risk groups.


Prenatal exposures to organophosphate ester metabolites and early motor development in the MADRES cohort.
Organophosphate esters (OPEs) are increasingly considered neurotoxicants which may impact gross and fine motor development. We evaluated associations between prenatal OPE exposures and infant motor development. Third trimester urinary concentrations of nine OPE metabolites were measured in 329 mother-infant dyads participating in the Maternal And Developmental Risks from Environmental and Social Stressors (MADRES) cohort. Child gross and fine motor development at 6, 9, 12, and 18-months were assessed with the Ages and Stages Questionnaire-3 (ASQ-3) and operationalized in models using dichotomous instrument-specific cutoffs for typical motor development. Five OPE metabolites with >60% detection were specific-gravity-adjusted, natural log-transformed, and modeled continuously, while four metabolites with <60% detection were modeled dichotomously (detected/not-detected). We fit mixed effects logistic regression between OPE metabolites and fine/gross motor development and assessed sex-specific effects using a statistical interaction term and sex-stratified models. Among children, 31% and 23% had gross and fine motor scores, respectively, below the ASQ-3 at-risk cutoffs at least once across infancy. A doubling in prenatal diphenyl phosphate (DPHP) exposure was associated with 26% increased odds of potential fine motor delays (ORfine = 1.26, 95% CI: 1.02, 1.57, p = 0.04). We also observed significant interactions by infant sex for associations of detected dipropyl phosphate (DPRP) with gross motor development (pinteraction = 0.048) and detected bis(1-chloro-2-propyl) phosphate (BCIPP) with fine motor development (pinteraction = 0.02). Females had greater odds of potential motor delays for both detected DPRP (females vs males ORgross (95% CI) = 1.48 (0.71, 3.09), p = 0.30 vs 0.27 (0.06, 1.29), p = 0.10) and detected BCIPP (females vs males ORfine (95% CI) = 2.72 (1.27, 5.85), p = 0.01 vs 0.76 (0.31, 1.90), p = 0.56). There were no other significant associations between other metabolites and motor development, despite similar patterns. We found evidence of adverse effects of prenatal OPE exposures on infant motor development with greater adverse effects among female infants with some OPE metabolites.


Role of Glitazars in atherogenic dyslipidemia and diabetes: Two birds with one stone?
A triad of high triglycerides, low high-density lipoprotein (HDL) cholesterol, and elevated small dense low-density lipoprotein particles occurring in a patient with type 2 diabetes is referred to atherogenic diabetic dyslipidemia (ADD). Despite statin therapy, a significant residual risk remains potentially attributable to increased triglyceride concentration and low HDL cholesterol, a characteristic hallmark of ADD. Current therapeutic options in reducing this residual risk include nicotinic acid, omega 3 fatty acids, and selective peroxisome proliferator-activated receptor-alpha (PPAR) agonists (fibrates). These drugs are limited in their potential either by lack of evidence to support their role in reducing cardiovascular events or due to their side effects. This review details their current status and also the role of new glitazar, saroglitazar adual PPARα/γ agonist with predominant PPARα activity in the management of ADD.


Pushing property limits in materials discovery via boundless objective-free exploration.
Materials chemists develop chemical compounds to meet often conflicting demands of industrial applications. This process may not be properly modeled by black-box optimization because the target property is not well defined in some cases. Herein, we propose a new algorithm for automated materials discovery called BoundLess Objective-free eXploration (BLOX) that uses a novel criterion based on kernel-based Stein discrepancy in the property space. Unlike other objective-free exploration methods, a boundary for the materials properties is not needed; hence, BLOX is suitable for open-ended scientific endeavors. We demonstrate the effectiveness of BLOX by finding light-absorbing molecules from a drug database. Our goal is to minimize the number of density functional theory calculations required to discover out-of-trend compounds in the intensity-wavelength property space. Using absorption spectroscopy, we experimentally verified that eight compounds identified as outstanding exhibit the expected optical properties. Our results show that BLOX is useful for chemical repurposing, and we expect this search method to have numerous applications in various scientific disciplines.


Therapeutic options in the management of colon cancer: 2005 update.
Recently, major developments in the treatment of colon cancer have emerged. These developments include improvements in surgical technique and staging and the introduction of new molecularly targeted pharmacologic agents. Improvements in surgical management involve enhanced staging techniques, allowing more accurate determination of risk of recurrence. Newer agents, such as oxaliplatin, cetuximab, and bevacizumab, now are approved for the treatment of colon cancer. The data associated with use of oxaliplatin in adjuvant and metastatic settings continue to mature; survival benefits are expected to become more fully apparent in the next two years. Bevacizumab, a monoclonal antibody that neutralizes vascular endothelial growth factor, when combined with irinotecan, 5-fluorouracil, and leucovorin (IFL), was superior to IFL alone in achieving median and progression-free survival. Cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, when given in combination with irinotecan, achieved an increased objective response and increased time to progression, compared with cetuximab alone, in patients refractory to irinotecan-containing regimens. In addition to surgical and pharmacologic developments, the recognition that genetics and molecular markers play an important role in carcinogenesis has heightened research to integrate this knowledge into practice. Nurses play a pivotal role in the care of patients with colon cancer and must be conversant in the new advances in treatment.


Imaging frontostriatal function in ultra-high-risk, early, and chronic schizophrenia during executive processing.
Individuals experiencing prodromal symptoms of schizophrenia (ultra-high-risk group) demonstrate impaired performance on tasks of executive function, attention, and working memory. The neurobiological underpinnings of such executive deficits in ultra-high-risk individuals remains unclear. We assessed frontal and striatal functions during a visual oddball continuous performance task, in ultra-high-risk, early, and chronic schizophrenic patients with the use of functional magnetic resonance imaging. Cross-sectional case-control design. Community; outpatient clinic. Patients Fifty-two individuals (control, n = 16; ultra-high risk, n = 10; early, n = 15; chronic, n = 11) from a referred clinical sample and age- and sex-matched control volunteers underwent scanning. Percentage of active voxels and percentage signal change calculated for the anterior cingulate gyrus (ACG), middle frontal gyrus (MFG), inferior frontal gyrus (IFG), basal ganglia, and thalamus. Performance on the visual oddball task was measured with percentage of hits and d' (a measure based on the hit rate and the false-alarm rate). The ultra-high-risk group showed significantly smaller differential activation between task-relevant and task-irrelevant stimuli in the frontal regions (ACG, IFG, MFG) than the control group. Frontostriatal activation associated with target stimuli in the early and chronic groups was significantly lower than the control group, while the ultra-high-risk group showed a trend toward the early group. Our findings suggest that prefrontal function begins to decline before the onset of syndromally defined illness and hence may represent a vulnerability marker in assessing the risk of developing psychotic disorders among ultra-high-risk individuals.


The Workforce Task Force report: clinical implications for neurology.
The American Academy of Neurology Workforce Task Force (WFTF) report predicts a future shortfall of neurologists in the United States. The WFTF data also suggest that for most states, the current demand for neurologist services already exceeds the supply, and by 2025 the demand for neurologists will be even higher. This future demand is fueled by the aging of the US population, the higher health care utilization rates of neurologic services, and by a greater number of patients gaining access to the health care system due to the Patient Protection and Affordable Care Act. Uncertainties in health care delivery and patient access exist due to looming concerns about further Medicare reimbursement cuts. This uncertainty is set against a backdrop of Congressional volatility on a variety of issues, including the repeal of the sustainable growth rate for physician reimbursement. The impact of these US health care changes on the neurology workforce, future increasing demands, reimbursement, and alternative health care delivery models including accountable care organizations, nonphysician providers such as nurse practitioners and physician assistants, and teleneurology for both stroke and general neurology are discussed. The data lead to the conclusion that neurologists will need to play an even larger role in caring for the aging US population by 2025. We propose solutions to increase the availability of neurologic services in the future and provide other ways of meeting the anticipated increased demand for neurologic care.


Pediatric provider processes for behavioral health screening, decision making, and referral in sites with colocated mental health services.
Validated behavioral health (BH) screens are recommended for use at well-child visits. This study aimed to explore how pediatricians experience and use these screens for subsequent care decisions in primary care. The study took place at 4 safety net health centers. Fourteen interviews were conducted with pediatricians who were mandated to use validated BH screens at well-child visits. Interview questions focused on key domains, including clinic BH context, screening processes, assessment of screening scores, and decision making about referral to mental health services. Qualitative analysis used the Framework Approach. A variety of themes emerged: BH screens were well accepted and valued for the way they facilitated discussion of mental health issues. However, screening results were not always used in the way that instrument designers intended. Providers' beliefs about the face validity of the instruments, and their observations about performance of instruments, led to discounting scored results. As a result, clinical decisions were made based on a variety of evidence, including individual item responses, parent or patient concerns, and perceived readiness for treatment. Additionally, providers, although interested in expanding their mental health discussions, perceived a lack of time and of their own skills to be major obstacles in this pursuit. Screens act as important prompts to stimulate discussion of BH problems, but their actual scored results play a variable role in problem identification and treatment decisions. Modifications to scheduling policies, additional provider training, and enhanced collaboration with mental health professionals could support better BH integration in pediatric primary care.


Proteus vulgaris agglutination by cystic fibrosis sera.
The factor in sera of patients with cystic fibrosis (CF) and their parents which agglutinates Proteus vulgaris has characteristics similar to those of IgG antibody to this organism. Sera of patients without CF who have P. vulgaris infections agglutinate the organism similarly. At present there are too many false-positives in a control population for the test to be widely useful for heterozygote identification.


Beef production efficiency.
In the production of high quality protein, feed grains will continue to be used to finish cattle for market as long as economics dictates. Production systems could be developed that would make ruminant animals less competitive with humans for feed grains, but the costs of instituting such programs would be prohibitive. Sufficient genetic variation exists either between or within breeds for the cattle population to be adapted to new management programs and for current methods of beef production to be significantly improved.


Development and validation of the Family Health Behavior Scale.
The purpose of the current study was to develop a psychometrically sound, parent-report measure of family and child behaviors related to obesity in children between 5- and 12-years-old. Item generation, item selection, and initial exploratory factor analysis yielded a 27-item measure called the Family Health Behavior Scale (FHBS). The FHBS contains four subscales measuring health-promoting family behaviors, obesogenic behaviors, meal-time routines, and family physical activity habits. Parent ratings on the FHBS were shown to predict their child's weight classification. The FHBS also demonstrated adequate internal consistency and temporal stability. The results of the study suggest that the FHBS is a promising measure of family eating and physical activity habits related to obesity in children.


Visualization of stimulated nerve endings by preferential calcium accumulation of mitochondria.
Calcium was detected by X-ray microanalysis in the mitochondria of electrically stimulated nerve endings. The phenomenon described here offers a simple means for identifying the stimulated nerve endings in the electron microscope and appears to be a promising new method for following spontaneous and drug-stimulated translocation of calcium in relation to the regulation of neurotransmitter release.


Occult hepatitis B virus infection and its clinical implications.
Occult hepatitis B virus (HBV) infection is characterized by presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg). Serum HBV level is usually less than 104 copies/mL in these patients. Diagnosis of occult HBV infection requires sensitive HBV-DNA PCR assay. Several possibilities have been hypothesized as the mechanisms of occult HBV infection. These include: (i) mutations of HBV-DNA sequence; (ii) integration of HBV-DNA into host's chromosomes; (iii) infection of peripheral blood mononuclear cells by HBV; (iv) formation of HBV-containing immune complex; (v) altered host immune response; and (vi) interference of HBV by other viruses. The precise prevalence of occult HBV infection remains to be defined. The clinical implications of occult HBV infection involve different clinical aspects. First of all, occult HBV infection harbours potential risk of HBV transmission through blood transfusion, haemodialysis, and organ transplantation. Second, it may serve as the cause of cryptogenic liver disease, contribute to acute exacerbation of chronic hepatitis B, or even fulminant hepatitis. Third, it is associated with development of hepatocellular carcinoma. Fourth, it may affect disease progression and treatment response of chronic hepatitis C. Most of the previous studies utilized retrospective observation without control groups, and lacked direct association of occult HBV infection with specific pathological changes and disease progression. Highly sensitive, quantitative, and functional molecular analyses of HBV, combined with a well-designed prospective clinical assessment will provide the best approach for the future study of occult HBV infection.


Platelet retention in glass bead columns: adhesion to glass and subsequent platelet-platelet interactions.
In normal heparinized blood, the retention of platelets in glass bead columns was low in the first 1 or 2 ml, increasing to more than 80% by the 4th or 5th ml. Prior flushing of the columns with platelet-poor plasma or saline lowered retention in all 5 ml. Additional studies were carried out with a two-stage procedure in which a sample of blood (A) was pumped through a column, immediately flushed out with saline or plasma, and followed by a second blood sample (B). When as little as 1 ml of blood A preceded the flushing solution, retention was very high in all 5 ml of the subsequent blood B. This enhancement of retention in B occurred, providing blood A contained platelets (other than thrombasthenic), fibrinogen, and adequate divalent cations. Enhancement did not require von Willebrand factor (vWF) in A, nor was ADP necessary, since enhancement occurred even when heparinized blood as A contained prostaglendin E1 (PGE1) or creatine phosphokinase with creatine phosphate (CPK-CP). However, the presence of PGE1 or CPK-CP in the plasma used to flush the columns prevented the enhancement of retention in the first milliliter of B. Retention in the first milliliter of B (following normal blood as A and saline or normal plasma for flushing) was high when B was afibrinogenemic, moderately high when B contained PGE1 or CPK-CP, and low in thrombasthenic, EDTA, or vWF-deficient blood. Retention declined in subsequent milliliters of PGE1 or CPK-CP blood and remained low in thrombasthenic, vWF-deficient, or EDTA blood. Our findings suggest that (1) the platelets in A adhere to glass; this adhesion requires fibrinogen but not vWF or ADP; (2) the adherent platelets release ADP and become sticky; (3) adhesion of platelets in the first milliliter of B to the sticky platelets from A requires vWF and divalent cations but not ADP; (4) retention is maintained thereafter by repetitive platelet-platelet interactions involving ADP release, alteration of adherent platelets by released ADP, and adhesion of further platelets to these ADP-altered platelets which requires vWF.


Combining region- and network-level brain-behavior relationships in a structural equation model.
Brain-behavior associations in fMRI studies are typically restricted to a single level of analysis: either a circumscribed brain region-of-interest (ROI) or a larger network of brain regions. However, this common practice may not always account for the interdependencies among ROIs of the same network or potentially unique information at the ROI-level, respectively. To account for both sources of information, we combined measurement and structural components of structural equation modeling (SEM) approaches to empirically derive networks from ROI activity, and to assess the association of both individual ROIs and their respective whole-brain activation networks with task performance using three large task-fMRI datasets and two separate brain parcellation schemes. The results for working memory and relational tasks revealed that well-known ROI-performance associations are either non-significant or reversed when accounting for the ROI's common association with its corresponding network, and that the network as a whole is instead robustly associated with task performance. The results for the arithmetic task revealed that in certain cases, an ROI can be robustly associated with task performance, even when accounting for its associated network. The SEM framework described in this study provides researchers additional flexibility in testing brain-behavior relationships, as well as a principled way to combine ROI- and network-levels of analysis.


Virtual microscopy and digital cytology: state of the art.
The paper approaches a new technological scenario relevant for the introduction of the digital cytology (D-CYT) in the health service. A detailed analysis of the state of the art on the status of the introduction of D-CYT in the hospital and more in general in the dispersed territory has been conducted. The analysis was conducted in a form of review and was arranged into two parts: the first part focused on the technological tools needed to carry out a successful service (client server architectures, e-learning, quality assurance issues); the second part focused on issues oriented to help the introduction and evaluation of the technology (specific training in D-CYT, health technology assessment in-routine application, data format standards and picture archiving computerized systems (PACS) implementation, image quality assessment, strategies of navigation, 3D-virtual-reality potentialities). The work enlightens future scenarios of actions relevant for the introduction of the technology.


Treatment of Down syndrome-associated craniovertebral junction abnormalities.
Operative intervention for craniovertebral junction (CVJ) instability in patients with Down syndrome has become controversial, with reports of a low incidence of associated neurological dysfunction and high surgical morbidity rates. The authors analyzed their experience in light of these poor results and attempted to evaluate differences in management. Medical and radiographic records of 36 consecutive patients with Down syndrome and CVJ abnormalities were reviewed. The most common clinical complaints included neck pain (15 patients) and torticollis (12 patients). Cervicomedullary compression was associated with ataxia and progressive weakness. Hyperreflexia was documented in a majority of patients (24 cases), and 13 patients suffered from varying degrees of quadriparesis. Upper respiratory tract infection precipitated the presentation in five patients. Four patients suffered acute neurological insults after a minor fall and two after receiving a general anesthetic agent. Atlantoaxial instability was the most common radiographically observed abnormality (23 patients), with a rotary component present in 14 patients. Occipitoatlantal instability was also frequently observed (16 patients) and was coexistent with atlantoaxial dislocation in 15 patients. Twenty individuals had bone anomalies, the most frequent of which was os odontoideum (12 patients) followed by atlantal arch hypoplasia and bifid anterior or posterior arches (eight patients). Twenty-seven patients underwent surgical procedures without subsequent neurological deterioration, and a 96% fusion rate was observed. In five of 11 patients basilar invagination was irreducible and required transoral decompression. Overall, 24 patients enjoyed good or excellent outcomes. The results of this series highlight the clinicopathological characteristics of CVJ instability in patients with Down syndrome and suggest that satisfactory outcomes can be achieved with low surgical morbidity rates.


Viscoelastic Testing in Trauma.
Traumatic-induced coagulopathy (TIC) is a complex condition which develops both as a response to trauma as well as to clinical care interventions. Accurate and timely diagnostics are necessary to enable therapy aimed at correction of TIC. Viscoelastic hemostatic assays (VHA) are increasingly recognized for their potential to diagnose TIC as well as for guidance of treatment. This narrative review focuses on the evidence of the use of VHAs to diagnose TIC, to monitor efficacy of treatment of TIC during bleeding and to prognosticate outcome. Pitfalls of the use of VHA are also discussed.


Ciprofloxacin therapy in cystic fibrosis.
There is great need for an oral agent that could be used to treat pulmonary exacerbations in patients with cystic fibrosis. In this study, the use of oral ciprofloxacin as sole therapy was evaluated in 18 patients with 39 infectious episodes; 13 episodes were classified as severe, 19 were classified as moderate, and seven were classified as mild. Patients ranged in age from eight to 36 years (mean, 23 years). Dosage varied according to severity of disease, body size, and the susceptibility of the Pseudomonas isolate to ciprofloxacin; the dose ranged from 750 to 2,250 mg daily (mean, 1,800 mg). Ten patients received one course of ciprofloxacin, and eight received repeated courses. The overall clinical response rate was 82 percent. There was a response to the initial treatment course in 96 percent of the patients. Those in whom therapy failed had been re-treated with ciprofloxacin and were severely ill. Failure to respond correlated poorly with pretreatment minimal inhibitory concentration (MIC) values (0.6 microgram/ml for failures versus 0.4 microgram/ml for responses). Pseudomonas could not be eradicated from the sputum of any of the patients, although there was a marked reduction in purulence and bacterial counts. In general, patients who did not require re-treatment for three months would again have susceptible organisms. When organisms became resistant to ciprofloxacin (MIC greater than 2 micrograms/ml), they showed no concomitant new aminoglycoside or beta-lactam resistance. No serious toxicity occurred in any of the 39 episodes of treatment. In seven patients treated with combination therapy (tobramycin or azlocillin), the infecting organisms were reduced in number, but eradication of Pseudomonas generally could not be achieved. Increases in MIC occurred during combination therapy. Ciprofloxacin is a major advance in the treatment of bronchopulmonary infection in patients with cystic fibrosis.


[Energy intake, maternal nutritional status and intrauterine growth retardation].
To explore the association between low caloric intake during pregnancy and intrauterine growth retardation (IUGR), a case-control study with 264 cases and 892 controls was conducted in three maternity hospitals in Mexico City from January to August 1995. Nutritional information on pregnancy was recorded using a previously validated food frequency questionnaire. After adjusting for other known maternal risk factors in the non-conditional logistic regression analysis, for the total sample, caloric intake did not present a direct effect on IUGR (OR: 0.99; CI 95%: 0.99-1.00). However the odds ratios were as follows for women: with low pre-gestational weight (OR: 2.31; CI 95%: 1.59-3.36), in first gestation (OR: 1.72; CI 95%: 1.18-2.51), with low birth weight infants (OR: 3.54; CI 95%: 1.93-6.46), and presenting hypertension during pregnancy (OR: 1.61; CI 95%: 1.00-2.59).


From dusk till dawn: the Arabidopsis thaliana sugar starving responsive network.
Plant growth and development are tightly controlled by photosynthetic carbon availability. The understanding of mechanisms governing carbon partitioning in plants will be a valuable tool in order to satisfy the rising global demand for food and biofuel. The goal of this study was to determine if sugar starvation responses were transcriptionally coordinated in Arabidopsis thaliana. A set of sugar-starvation responsive (SSR) genes was selected to perform a co-expression network analysis. Posteriorly, a guided-gene approach was used to identify the SSR-network from public data and to discover candidate regulators of this network. In order to validate the SSR network, a global transcriptome analysis was realized on three A. thaliana starch-deficient mutants. The starch-deficient phenotype in leaves induces sugar starvation syndrome at the end of the night due to the absence of photosynthesis. Promoter sequences of genes belonging to the SSR-network were analyzed in silico reveling over-represented motifs implicated in light, abscisic acid, and sugar responses. A small cluster of protein encoding genes belonging to different metabolic pathways, including three regulatory proteins, a protein kinase, a transcription factor, and a blue light receptor, were identified as the cornerstones of the SSR co-expression network. In summary, a large transcriptionally coordinated SSR network was identified and was validated with transcriptional data from three starch-deficient mutant lines. Candidate master regulators of this network were point out.


Elevated Serum Endocan Levels in Patients with Rosacea: A New Therapeutic Target?
Rosacea is a chronic inflammatory skin disease whose etiopathogenesis is still unknown. Previous studies have shown a relationship between certain inflammatory disorders and serum endocan levels. Endocan (previously known as endothelial cell-specific molecule 1) might play a role in the pathogenesis of various inflammatory diseases. Our study aimed to evaluate serum endocan levels in patients with rosacea to investigate the association of endocan with the demographic data. The study recruited individuals aged ≥18 years who voluntarily agreed to participate in the study. The participants included 37 women (mean age: 48.29 ± 12.08 years) and 13 men (mean age: 52.23 ± 13.34 years) diagnosed with rosacea, and 37 women (mean age: 49.18 ± 16.6 years) and 13 men (mean age: 53.69 ± 11.30 years) selected as controls. Both groups were matched according to age and sex. The rosacea diagnosis was based on clinical examination findings, and serum endocan levels were measured using the method of enzyme-linked immunosorbent assay (ELISA). The statistical significance of the data was determined by the Mann-Whitney U test, and a value of P < 0.05 was considered statistically significant. Serum endocan levels differed significantly between the patients with rosacea and the control group (P < 0.05). Circulating endocan might be a new marker related to disease progression in patients with rosacea. Further investigation is needed to determine whether endocan levels could become a new therapeutic target in rosacea, a disease that still cannot be fully cured.


Probiotics and the prevention of necrotizing enterocolitis.
Immaturity of the host immune system and alterations in the intestinal microbiome appear to be key factors in the pathogenesis of necrotizing enterocolitis (NEC). The aim of this paper is to weigh the evidence for the use of probiotics to prevent NEC in premature infants. Animal studies, randomized controlled trials, observational cohort studies and meta-analyses involving administration of probiotic products for the prevention of NEC were reviewed. This review of the evidence summarizes the available preclinical and clinical data. In animal models probiotic microbes alter the intestinal microbiome, decrease inflammation and intestinal permeability and decrease the incidence and severity of experimental NEC. In randomized, placebo-controlled trials and cohort studies of premature infants, probiotic microbes decrease the risk of NEC, death and sepsis. Evidence is strong for the prevention of NEC with the use of combination probiotics in premature infants who receive breast milk. The potential risks and benefits of probiotic administration to premature infants should be carefully reviewed with parents. Therapeutic. I.


Diagnosis of congenital vascular malformations of the extremities: new perspectives.
Congenital vascular malformation (CVM's) have traditionally been evaluated angiographically. Unfortunately, this approach does not always give definitive information about the various components, particularly microfistulous lesions and venous angiomata, and it provides little physiologic information. Furthermore, it is expensive, invasive, and is not needed to guide therapy in the majority of patients who either do not need or will not benefit from surgery or embolotherapy. We propose a different approach which begins initially with simple noninvasive screening tests, then selectively uses labelled-albumin microspheres to quantify the AV shunt fraction and/or magnetic resonance imaging (MRI) to define the anatomic extent and involvement of adjacent structures. This approach gives sufficient anatomic and physiologic information in the vast majority of cases to allow reasonable prognostication and to guide future therapy. Angiography is then reserved for patients identified as probably having localized lesions or for those with more extensive CVM's whose symptoms ultimately justify therapeutic intervention.


Prenatal diagnosis in congenital contractural arachnodactyly.
Congenital contractural arachnodactyly (CCA) is a heritable connective tissue disorder caused by defects in the gene encoding fibrillin-2 (FBN2). People with CCA typically have a marfanoid habitus, flexion contractures, severe kyphoscoliosis, abnormal pinnae, and muscular hypoplasia. Because of the relative infrequency of the syndrome and its generally mild to moderate severity, prenatal diagnosis had not previously been sought. Here we report prenatal diagnosis in a family with CCA. Because the course of the disease in the proband was rather severe, she had requested genetic counseling as early as age 17. She delayed childbearing until prenatal diagnosis for CCA became possible. This decision was supported by her mother and later her husband. Because she shared the same genotype with her husband, genetic linkage analysis of this family did not alter the a priori 50% risk of having an affected child. The possibility of unambiguously ascertaining the affected status of a fetus homozygous for the tested FBN2 marker was sufficient for the family to pursue prenatal diagnosis. This case strongly points to the importance of informed decisions now that genetic testing is becoming commonplace.


Neuropsychiatric symptoms in Latino elders with dementia or cognitive impairment without dementia and factors that modify their association with caregiver depression.
The purpose of this study was to determine neuropsychiatric symptom frequency and intensity in demented and cognitively impaired but not demented Latino elderly persons, evaluate whether overall neuropsychiatric symptom intensity is associated with higher levels of caregiver depression, and identify factors that modify the relationship between neuropsychiatric symptoms and caregiver depression. Ninety-five elderly Latinos with dementia or cognitive impairment but not dementia (CIND), all of whom were identified through an ongoing epidemiological cohort study, and their informal caregivers participated in the study. Caregivers were interviewed in their homes, in either Spanish or English. The Neuropsychiatric Inventory was used to assess neuropsychiatric disturbances. For most neuropsychiatric symptoms, prevalence and intensity were significantly higher in the demented group compared with the CIND group. The overall neuropsychiatric symptom intensity score was significantly associated with caregiver depression. The strength and direction of the association of neuropsychiatric symptoms with caregiver depression was found to vary by three factors: whether the caregiver was the care recipient's spouse, whether the care recipient had dementia or CIND, and the care recipient's age. Neuropsychiatric symptoms may play a significant role in caregiver depression among Latino families. However, the impact of neuropsychiatric disturbances on Latino caregivers may differ depending on characteristics of both the caregiver and care recipient. The adverse impact of neuropsychiatric symptoms on caregivers of elderly persons with CIND has not been previously reported and deserves further study.


[Construction of the plasmid encoding the fusion protein of hepatocyte growth factor and red fluorescent protein].
In order to trace the expression of exogenous hepatocyte growth factor (HGF) in eukaryotic cells exactly, a recombinant plasmid that expresses the fusion protein of HGF and red fluorescent protein (RFP) was constructed. The gene encoding HGF without stop code was amplified from pMD19-T-HGF by PCR technique and then cloned in pDsRed-express-N1. The recombinant plasmid (pDsRed-HGF) was identified by restriction endonuclease enzyme analysis and DNA sequence analysis. pDsRed-HGF was transfected into 293T cells. The expression of HGF mRNA, HGF and red fluorescent protein was detected. The results showed that the target gene sequence in pDsRed-HGF was completely in conformity with HGF cDNA in GenBank, and it was expressed highly in 293T cells. In this study, pDsRed-HGF was successfully constructed and expressed in eukaryotic cells.


[Otoplasties for prominent ears].
The authors describe a personal otoplasty technique based on several well known methods. This simple technique is performed as an outpatient procedure without chondrotomy, allowing controlled adjustment of the correction regardless of the type of deformity and ensures reliable long-term results. After describing the various steps of the operation, the authors present the rare complications which may occur.


Solid-pseudopapillary tumor of the pancreas: immunohistochemical localization of neuroendocrine markers and CD10.
To clarify the neuroendocrine differentiation and CD10 expression in solid-pseudopapillary tumors (SPTs) of the pancreas, we performed immunohistochemical analysis in 19 such tumors, including one solid-pseudopapillary carcinoma (SPC), along with 20 pancreatic neuroendocrine tumors (PNTs), six acinar cell carcinomas (ACCs), and one pancreatoblastoma (PB). We used antisera directed against CD56, synaptophysin, protein gene product 9.5, the alpha-subunit of Go protein, chromogranin A, CD10, trypsin, chymotrypsin, various cytokeratins (CKs), CA19-9, vimentin, and alpha-1-antitrypsin (AAT). All SPTs exhibited immunoreactivity for CD56 and CD10, and 15 expressed other neuroendocrine markers focally with the exception of chromogranin A. Frequent clustering of synaptophysin-positive cells was noted. Two cases contained a peculiar nodule that cytomorphologically and immunohistochemically resembled PNT. CD10-positive cells were scarce in one SPC. PNTs were CD56-positive, but often with faint intensity, and staining for other neuroendocrine markers, including chromogranin A, was diffusely positive. CD10 was detected, mostly in a focal pattern, in five PNTs. Pan-CK, CK8, CK18, and CK19 were more frequently demonstrated in PNT than SPT. Vimentin and AAT were often identified in PNT as well and were not specific for SPT. ACCs were CD56-negative, with the exception of one case designated as a mixed acinar-endocrine carcinoma. PB was focally positive for CD56 at the periphery of the tumor nests. Four ACCs and one PB exhibited focal CD10 reactivity. This study demonstrated the unique immunohistochemical features of SPT. Our results also suggest that SPT exhibits, at least focally, neuroendocrine differentiation, and that these neuroendocrine markers and CD10 are diagnostically useful.


Geochemical association of Pu and Am in selected host-phases of contaminated soils from the UK and their susceptibility to chemical and microbiological leaching.
Understanding the biogeochemical behaviour and potential mobility of actinides in soils and groundwater is vital for developing remediation and management strategies for radionuclide-contaminated land. Pu is known to have a high Kd in soils and sediments, however remobilization of low concentrations of Pu remains a concern. Here, some of the physicochemical properties of Pu and the co-contaminant, Am, are investigated in contaminated soils from Aldermaston, Berkshire, UK, and the Esk Estuary, Cumbria, UK, to determine their potential mobility. Sequential extraction techniques were used to examine the host-phases of the actinides in these soils and their susceptibility to microbiological leaching was investigated using acidophilic sulphur-oxidising bacteria. Sequential extractions found the majority of (239,240)Pu associated with the highly refractory residual phase in both the Aldermaston (63.8-85.5 %) and Esk Estuary (91.9-94.5%) soils. The (241)Am was distributed across multiple phases including the reducible oxide (26.1-40.0%), organic (45.6-63.6%) and residual fractions (1.9-11.1%). Plutonium proved largely resistant to leaching from microbially-produced sulphuric acid, with a maximum 0.18% leached into solution, although up to 12.5% of the (241)Am was leached under the same conditions. If Pu was present as distinct oxide particles in the soil, then (241)Am, a decay product of Pu, would be expected to be physically retained in the particle. The differences in geochemical association and bioleachability of the two actinides suggest that this is not the case and hence, that significant Pu is not present as distinct particles. These data suggest the majority of Pu in the contaminated soils studied is highly recalcitrant to geochemical changes and is likely to remain immobile over significant time periods, even when challenged with aggressive "bioleaching" bacteria.


Operation debrief: a SHARP improvement in performance feedback in the operating room.
To explore the current status of performance feedback (debriefing) in the operating room and to develop and evaluate an evidence-based, user-informed intervention termed "SHARP" to improve debriefing in surgery. Effective debriefing is a key educational technique for optimizing learning in surgical settings. However, there is a lack of a debriefing culture within surgery. Few studies have prospectively evaluated educational interventions to improve the quality and quantity of performance feedback in surgery. This was a prospective pre- and post-study of 100 cases involving 22 trainers (attendings) and 30 surgical residents (postgraduate years 3-8). A trained researcher assessed the quality of debriefings provided to the trainee using the validated Objective Structured Assessment of Debriefing (OSAD) tool alongside ethnographic observation. Following the first 50 cases, an educational intervention termed "SHARP" was introduced and measures repeated for a further 50 cases. User satisfaction with SHARP was assessed via questionnaire. Twenty percent of the cases were observed independently by a second researcher to test interrater reliability. Interrater reliability for OSAD was excellent (ICC = 0.994). Objective scores of debriefing (OSAD) improved significantly after the SHARP intervention: median pre = 19 (range, 8-31); median post = 33 (range, 26-40), P < 0.001. Strong correlations between observer (OSAD) and trainee rating of debriefing were obtained (median ρ = 0.566, P < 0.01). Ethnographic observations also supported a significant improvement in both quality and style of debriefings. Users reported high levels of satisfaction in terms of usefulness, feasibility, and comprehensiveness of the SHARP tool. SHARP is an effective and efficient means of improving performance feedback in the operating room. Its routine use should be promoted to optimize workplace-based learning and foster a positive culture of debriefing and performance improvement within surgery.


Development of sleep spindle bursts during the first year of life.
Sleep spindles, as defined in the international electroencephalography (EEG) glossary, are distinguished from spindle bursts seen in the EEGs of premature infants. Classical sleep spindles do not occur in prematures. They first appear clearly in the EEG during slow wave sleep from the 4th week postterm (44 weeks conceptional age) and are normally present in all infants' EEGs by 9 weeks postterm. During the first year of life they may be of high voltage relative to their appearance in older children and adults and are commonly characterized by variable degrees of interhemispheric asymmetry and asynchrony. Individual differences are great. Some features of clinical significance are discussed.


Lenses axial space ray tracing measurement.
In order to achieve the precise measurement of the lenses axial space, a new lenses axial space ray tracing measurement (ASRTM) is proposed based on the geometrical theory of optical image. For an assembled lenses with the given radius of curvature r(n) and refractive index nn of every lens, ASRTM uses the annular laser differential confocal chromatography focusing technique (ADCFT) to achieve the precise focusing at the vertex position P(n) of its inner-and-outer spherical surface Sn and obtain the coordinate z(n) corresponding to the axial movement position of ASRTM objective, and then, uses the ray tracing facet iterative algorithm to precisely determine the vertex position P(n) of every spherical surface by these coordinates z(n), refractive index n(n) and spherical radius r(n), and thereby obtaining the lenses inner axial space d(n). The preliminary experimental results indicate that ASRTM has a relative measurement error of less than 0.02%.